1. Field of the Invention
The present invention relates generally to the preparation of fluorinated ethers, which are useful as inhalation anesthetics.
2. Description of Related Art
Desflurane is a well known compound with effective anesthetic properties. For example see E. I. Eger et al, Anesthesia and Analgesia, 1987, pp 971-973, 974-976, 977-982, 983-985, 1227-1229, 1230-1233 and 1312-1315.
This compound is mentioned in U.S. Pat. No. 3,897,502, where it is prepared by the direct fluorination of 2-difluoromethoxy-1,1,1-trifluoroethane in Freon E3 as solvent, using 20% fluorine gas in argon. The reaction took 13 hours and had to be carried out at −20° C. to −25° C. to control the exothermic process. This process would be difficult to scale up due to the slow reaction, low reaction temperature and expensive reagents. Also, it is known to those skilled in the art that special care needs to be taken since the interaction of fluorine gas with partially fluorinated hydrocarbons is liable to cause explosions.
Other methods available for synthesis of desflurane involve:                a) Reaction of CHCl2OCH2COCl and/or CHCl2OCHClCOCl with sulfur tetrafluoride (U.S. Pat. No. 4,855,511). This is a multistage process and involves handling of highly toxic gaseous reagent sulfur tetrafluoride.        b) Reaction of CF3CHClOCF2H (isoflurane) with potassium fluoride. This reaction can be carried out in the absence of solvent at 278° C. under a pressure of 500 psi in an autoclave (U.S. Pat. No. 4,874,901) or in presence of an aprotic solvent (like sulfolane) with a phase transfer catalyst (tetramethylammonium chloride) at 210° C. again under pressure (UK Patent Specification No. 2,219,292). These processes have to be operated at high pressure and at elevated temperature for a long period of time and hence suffer from high capital cost. In addition, these processes have a further disadvantage in that they are essentially batch processes.        c) Reaction of CF3CHClOCF2H (isoflurane) with bromine trifluoride at ambient temperature (U.S. Pat. No. 5,015,781). Although this process gives a good yield and the transformation is accomplished in a short time, the reagent bromine trifluoride which is prepared from fluorine and bromine, is a highly toxic and hazardous chemical, which can explode in contact with water or organic materials. Special care and engineering are required for safe use which makes handling it on a commercial scale quite difficult. Additionally BrF3 is an expensive fluorinating agent.        d) Reaction of CF3CH2OCF2H with a solid transition metal fluoride fluorinating agent, where the fluorinating agent is CoF3 (U.S. Pat. No. 6,054,626). This process, according to the examples listed therein, gives a low yield (30-40%) of crude desflurane which has to be further purified for use as an anesthetic.        e) Reaction of CF3CHClOCF2H (isoflurane) with HF in the presence of antimony pentachloride, alone or in combination with antimony trichloride (U.S. Pat. Nos. 5,026,924 and 6,800,786). This process suffers from several drawbacks, including the use of highly toxic and environmentally troublesome antimony salts which must be removed as an aqueous waste stream. The process also results in the formation of very difficult to separate byproducts, the removal of which results in increased energy consumption, and more significantly, results in a reduced yield of desflurane.        
Accordingly, an object of the present invention was to provide a process whereby fluorinated ethers, including desflurane, can be prepared on an industrial scale without significant problems.